Meka Penchala Narasimharao, Amatya Eva, Kaur Sukhmanjit, Banerjee Monimoy, Zuo Ang, Dobrowsky Rick T, Blagg Brian S J
Department of Chemistry and Biochemistry, 305 McCourtney Hall, The University of Notre Dame, Notre Dame, IN 46556, United States.
Department of Pharmacology and Toxicology Department, The University of Kansas, Lawrence, KS 66045, United States.
Bioorg Med Chem. 2022 Sep 15;70:116940. doi: 10.1016/j.bmc.2022.116940. Epub 2022 Jul 16.
KU-32 (2) and KU-596 (3), are first and second generation cytoprotective novologues that are derivatives of novobiocin (1), a heat shock protein 90 (Hsp90) C-terminal inhibitor. Although 2 and 3 improve mitochondrial bioenergetics and have demonstrated considerable cytoprotective activity, they contain a synthetically demanding noviose sugar. This issue was initially addressed by creating noviomimetics, such as KU-1202 (4), which replaced the noviose sugar with ether-linked cyclohexyl derivatives that retained some cytoprotective potential due to their ability to increase mitochondrial bioenergetics. Based on structure-activity relationship (SAR) studies of KU-1202 (4), the current study investigated 3'- and 4'-substituted cyclohexyl scaffolds as noviomimetics and determined their efficacy at increasing mitochondrial bioenergetic as a marker for cytoprotective potential.
KU-32（2）和KU-596（3）是第一代和第二代具有细胞保护作用的新诺菌素类似物，它们是新生霉素（1）的衍生物，新生霉素是一种热休克蛋白90（Hsp90）C端抑制剂。尽管2和3可改善线粒体生物能量学并已显示出相当大的细胞保护活性，但它们含有合成要求较高的诺维糖。最初通过创建新诺菌素模拟物来解决这个问题，例如KU-1202（4），它用醚连接的环己基衍生物取代了诺维糖，这些衍生物由于能够增加线粒体生物能量学而保留了一些细胞保护潜力。基于对KU-1202（4）的构效关系（SAR）研究，本研究调查了3'-和4'-取代的环己基支架作为新诺菌素模拟物，并确定了它们在增加线粒体生物能量方面作为细胞保护潜力标志物的功效。
